The long term objective of this Project is to understand how mutations in a general chaperone, a-B crystallin (CryAB) can affect global cardiac function during stress response signaling. The short term goal is to define the toxic mechanism of a mutant CryAB that causes the cardiovascular disease, Desmin-Related Cardiomyopathy (DRM), which is characterized by the appearance of electron-dense, proteinaceous aggregates in the sarcoplasm. We noted that, internal in the cardiomyocytes is a protein that reacts to an antibody detecting a toxic pre-amyloid oligomer (PAO), which is normally associated with the amyloid-based neurodegenerative diseases. Subsequently, we found that PAO is widespread in cardiomyocytes derived from human heart failure patients of different etiologies, implying that PAO may be an important mediator of cardiovascular disease. We think that the CryAB mutant mouse is a uniquely useful and relevant system that models a heretofore understudied phenomenon, accumulation of PAO, which is surprisingly widespread in both adult and pediatric heart failure. The goal, therefore, is to understand the pathogenic pathway that results in PAO accumulation, determine its toxicity in cardiomyocytes and define potential therapeutic targets or modalities for DCM and heart failure that occurs as a result of CryABR120G expression. Aim 1 will test the hypothesis that cardiomyocyte accumulation of pre-amyloid oligomer (PAO) is toxic and can directly cause heart failure. We will create a series of transgenic mice in which inducible PAO-genic protein expression is restricted to the cardiomyocytes and measure the cytotoxicity of expression as well as the pathogenic sequelae. Aim 2 will use inducible, cardiomyocyte-specific CryABR120G expression to test if PAO-mediated heart failure can be reversed. Aim 3 will express anti-apoptotic factors in CryABR120G DRM to determine if prevention of programmed cell death can, in the face of continuous CryABR120G expression, prevent heart failure or even reverse existing disease. We hypothesize that despite the occurrence of cardiomyocyte apoptosis in CryABR120G hearts, programmed cell death is peripheral and collateral to the primary etiology that transits the hearts toward failure in this model. These studies have the potential of establishing broad linkages between the neurodegenerative and cardiovascular diseases and identifying new targets for interfering with processes that occur in a broad range of cardiovascular disease.